The need for discovering and developing new antibiotics from higher plants continues to be an important area of health-related research as pathogenic microbes and parasites rapidly evolve resistance to commonly used antibiotics. A major objective of this research proposal is to investigate the chemistry, bioactivity and mode of action of novel plant-derived dithiacyclohexadiene (1,2-dithiins) polyacetylenes, thiophenes and derivatives. Preliminary studies have established that the thiarubrines, sulfur-containing polyacetylenes, are constituents of plants of the Asteraceae which are used by wild apes and humans for therapeutic purposes. The thiarubrines are effective in the dark and UV radiation against Candida albicans, and Aspergillus fumigatus at concentrations comparable to those of amphotericin B. The compounds are also active against nematodes and a variety of retroviruses. Since little is known about the distribution, chemistry, bioactivity and mode of action of naturally occurring dithiacyclohexadienes, we specifically propose to: (1) chemically screen a variety of medicinal plants and tissue cultures of the Asteraceae, for novel dithiapolyacetylenes and related bioactive metabolites (2) synthesize bioactive 1,2-dithiins and thiophenes for establishing structure-activity relations (SAR) and for large-scale in vivo testing and (3) investigate antimicrobial and nematocidal activities of the most potent dithiapolyacetylenes (natural or synthetic) in vitro and in vivo. (4) determine the toxicity of bioactive 1,2-dithiins in mice. The proposed studies should provide fundamental insights on the role of dithiacyclohexadienes as new antibiotics in the treatment of infectious and parasitic diseases.